JPH01275581A - Antitumor substance sf2582 derivative - Google Patents
Antitumor substance sf2582 derivativeInfo
- Publication number
- JPH01275581A JPH01275581A JP63103782A JP10378288A JPH01275581A JP H01275581 A JPH01275581 A JP H01275581A JP 63103782 A JP63103782 A JP 63103782A JP 10378288 A JP10378288 A JP 10378288A JP H01275581 A JPH01275581 A JP H01275581A
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- JP
- Japan
- Prior art keywords
- formula
- substance
- compound expressed
- compound
- reacted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000126 substance Substances 0.000 title claims abstract description 36
- 230000000259 anti-tumor effect Effects 0.000 title description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 33
- 150000001875 compounds Chemical class 0.000 abstract description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 7
- 230000018044 dehydration Effects 0.000 abstract description 5
- 238000006297 dehydration reaction Methods 0.000 abstract description 5
- 239000012442 inert solvent Substances 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 238000009833 condensation Methods 0.000 abstract description 4
- 230000005494 condensation Effects 0.000 abstract description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 150000003461 sulfonyl halides Chemical class 0.000 abstract description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 abstract 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- -1 sulfate ester Chemical class 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000001559 cyclopropyl group Chemical class [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000003459 sulfonic acid esters Chemical class 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- IUBMRJVNZLQSHU-FDJBSCRHSA-N monate-a Chemical compound C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(O)=O)OC1 IUBMRJVNZLQSHU-FDJBSCRHSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- ZNCXUFVDFVBRDO-UHFFFAOYSA-N pyridine;sulfuric acid Chemical compound [H+].[O-]S([O-])(=O)=O.C1=CC=[NH+]C=C1 ZNCXUFVDFVBRDO-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
【発明の詳細な説明】
１寒よΔ稚且π！
本発明は抗腫瘍活性を有する新規な抗生物質５Ｆ２５８
２物質の誘導体に関する。[Detailed description of the invention] 1 Cold, ΔChichi and π! The present invention provides a novel antibiotic 5F258 with antitumor activity.
Concerning derivatives of two substances.
従来の技術と ′すべさ課題
抗腫瘍性抗生物質５Ｆ２５８２Ａ及ＩＢ物質はストレプ
トフイセス属に属する一放＃ｌ薗ＳＦ２５８２株（機工
ａ薗寄第９６７２号）の培養液中から分離された新規抗
生物質であり１種々の腫瘍細胞に対し１者しい障害性を
示し、またマウスを用いた感染治療実験において、治療
効果を示す（本出願人の出願に係る特願昭６２−２９７
４７６号明細書参照）。Conventional technology and problems Antitumor antibiotics 5F2582A and IB substances are novel antibiotics isolated from the culture solution of Ichiho #1 Sonoyori strain SF2582 (Kikoa Sonoyori No. 9672) belonging to the genus Streptophyces. It is a substance that exhibits unique toxicity against various tumor cells, and also shows a therapeutic effect in infection treatment experiments using mice (Patent Application No. 1982-297 filed by the present applicant).
476 specification).
５Ｆ２５８２Ａ及びＢ物質は、詳細なＮＭＲスペクトル
及びＸＭ結晶構造解析を用いた発明者らのその後の研究
から９式［１１［］（ＳＦ２５８２Ａ）及１式１”１Ｖ
）（ＳＦ２５８２Ｂ）で示される化学構造を有すること
が明らかにされた。5F2582A and B substances were determined from the inventors' subsequent studies using detailed NMR spectra and XM crystal structure analysis to form 9 formulas [11[] (SF2582A) and 1 formula 1''1V.
) (SF2582B).
また、これら抗腫瘍性抗生物質５Ｆ２Ｓ８２Ａ及びＢ物
質を生産する５Ｆ２５８２株の培養液中には第３の成分
として式（Ｖ）で示される新規抗生物質５Ｆ２５８２Ｃ
物質が含まれることも明らかになった（本出願人の出願
に係る昭和６３年４月１９日出願の明細書参照）。In addition, the culture solution of the 5F2582 strain that produces these antitumor antibiotic substances 5F2S82A and B contains a novel antibiotic 5F2582C represented by formula (V) as a third component.
It has also become clear that a substance is included (see the specification filed on April 19, 1988, filed by the present applicant).
しかしながら、５Ｆ２５８２Ｃ物質は、その化学構造が
、５Ｆ２５８２Ａ及びＢ物質に極めて類似しているにも
ががわらず、その抗腫瘍活性は。However, although the chemical structure of the 5F2582C substance is very similar to the 5F2582A and B substances, its antitumor activity is limited.
５Ｆ２５８２Ａ及びＢ物質に比較し、微弱であって、低
濃度では実験腫瘍細胞系に、顕著な細胞障害性を示さな
い、従って貴重な天然物資源である５Ｆ２５８２Ｃ物質
を有効的に利用するには、単に微生物発酵技術により５
Ｆ２５８２Ｃ物質を製造するだけでなく、得られた５Ｆ
２５８２Ｃ物質に何らかの化学処理を加え、誘導体とし
て、抗腫瘍活性その他の生理活性を発現させることが望
まれた。In order to effectively utilize the 5F2582C substance, which is weak compared to the 5F2582A and B substances and does not show significant cytotoxicity to experimental tumor cell lines at low concentrations, it is therefore a valuable natural product resource. 5 simply by microbial fermentation technology
In addition to producing F2582C material, the obtained 5F
It was hoped that some kind of chemical treatment would be applied to the 2582C substance to create a derivative that would exhibit antitumor activity and other physiological activities.
本発明者らは、５Ｆ２５８２Ａ及びＢ物質と５Ｆ２５８
２Ｃ物質の抗腫瘍性の違いは１分子内における塩素原子
の存在に深く関連するものと考慮し、５Ｆ２５８２Ｃ物
質の化学修節により９分子内に、塩素原子と同様の活性
基を導入すれば、新らたな活性化合物が創製できるもの
と期待した。The present inventors discovered that 5F2582A and B substances and 5F258
Considering that the difference in antitumor properties of 2C substances is deeply related to the presence of chlorine atoms in one molecule, if active groups similar to chlorine atoms are introduced into 9 molecules by chemical modification of 5F2582C substances, We expected that we would be able to create new active compounds.
そこで本発明者らは、５Ｆ２５８２Ｃ物質を出発原料と
して、様々の化学反応性を調べ、誘導体を合成し、その
抗腫瘍性を調べたところ以下の式（１）で示される５Ｆ
２５８２Ｃ物質の硫酸エステル、及びアルキルもしくは
アリールスルホン酸エステルＭ及び１式（ＩＩ）で示さ
れるシクロプロパン誘導体が１強い抗腫瘍活性を示すこ
とを見い出した。Therefore, the present inventors investigated various chemical reactivities using the 5F2582C substance as a starting material, synthesized derivatives, and investigated its antitumor properties.
It has been found that the sulfate ester of substance 2582C, the alkyl or aryl sulfonic acid ester M, and the cyclopropane derivative represented by formula (II) 1 exhibit strong antitumor activity.
課題を解決するための手段
従って本発明の要皆とするところは、５Ｆ２５８２Ｃ物
質の化学変換により得られる弐Ｎ）〔式（１）中Ｘ及び
ＹはＲ３０２−基（式中Ｒはｐ−）リル基、メチル基も
しくは水酸基を表す）もしくは水素原子を表す。但しＸ
及びＹが同時に水素原子である場合を除く、〕で示され
る誘導体類、及び式［Ｉ［）
で示される新規な５Ｆ２５８２Ｃ物質誘導体にある６本
発明により提供される式（１）の化合物は５Ｆ２５８２
Ｃ物質を、不活性溶媒中、塩基の存在下、スルホン酸無
水物、スルホニルハライド。Means for Solving the Problems Therefore, the main point of the present invention is to obtain 2N obtained by chemical conversion of 5F2582C substance [in formula (1), X and Y are R302- group (in the formula, R is p-) represents a lyl group, methyl group, or hydroxyl group) or a hydrogen atom. However, X
and Y are hydrogen atoms at the same time, and the novel 5F2582C substance derivatives represented by the formula [I[)] The compound of formula (1) provided by the present invention is 5F2582
Substance C is mixed with sulfonic anhydride and sulfonyl halide in an inert solvent in the presence of a base.
無水硫酸−ピリジンコンプレックスもしくは、クロルス
ルホン酸と反応させ、水酸基をエステル化して得られる
ものである。使用される不活性溶媒の例として１例えば
ベンゼン、）ルエン、テトラヒドロフラン、ジオキサン
、ピリジン、Ｎ、Ｎ−ツメチルホルムアミド等があげら
れ、塩基の例として、トリエチルアミンで代表されるア
ルキル７ミン類及びピリジン塩基があげられる。エステ
ル化反応は、常温下に容易に進行するが、５Ｆ２５８２
Ｃ物質は式（Ｖ）に示したごとく分子内に２個の水酸基
を有するので、モノエステル製造にあたっては、制限さ
れた量、好ましくは１〜１．２倍モルのエステル化試薬
を用い、低温下に反応を行なわせることが効果的である
。It is obtained by reacting with a sulfuric anhydride-pyridine complex or chlorosulfonic acid to esterify the hydroxyl group. Examples of inert solvents used include benzene, toluene, tetrahydrofuran, dioxane, pyridine, N,N-trimethylformamide, etc., and examples of bases include alkyl heptamines represented by triethylamine and pyridine. Examples include bases. The esterification reaction easily proceeds at room temperature, but 5F2582
Substance C has two hydroxyl groups in the molecule as shown in formula (V), so when producing a monoester, a limited amount of esterification reagent, preferably 1 to 1.2 times the mole, is used, and the esterification is carried out at a low temperature. It is effective to allow the reaction to occur below.
次に本発明により提供される式（ＩＩ）の化合物は５Ｆ
２５８２Ｃ物質を不活性溶媒中脱水縮合剤と反応させ１
分子内脱水綿合を行なわせて得られる。用いられる脱水
縮合剤の例としては、トリフェニルホスフィン−７ゾ７
カルボン酸エステル系のごとき、比較的緩和な条件下に
進行するものが好ましく１本脱水縮合剤についてはｒ
５ｙｎｔｈｅｓｉｓ誌、１頁（１９！３４年）に記述さ
れている。Next, the compound of formula (II) provided by the present invention is 5F
2582C substance is reacted with a dehydration condensation agent in an inert solvent 1
Obtained by intramolecular dehydration. Examples of the dehydration condensation agent used include triphenylphosphine-7zo7
It is preferable to use one that proceeds under relatively mild conditions, such as a carboxylic acid ester-based dehydration condensation agent.
It is described in 5ynthesis magazine, page 1 (19!34).
寒嵐霞
以下に１本発明により提供される誘導体の有用性を実証
するものとして化合物製造の実施例、及ｖＰ−３８８白
血＠細胞障害活性及びマウスＰ−３８８白血病治療実験
の結果（第１表及び第２衰）を示す。Below are examples of compound production as demonstrations of the usefulness of the derivatives provided by the present invention, and results of vP-388 leukemia@cytotoxic activity and mouse P-388 leukemia treatment experiments (Table 1). and second decay).
治療実験は、腹腔内にＰ−３８８腫瘍細胞を移植したマ
ウスに試験化合物を１日１回、２日間腹腔内投与して行
ない、その効果はＩＬＳ（％）で表示した。The therapeutic experiment was conducted by intraperitoneally administering the test compound once a day for 2 days to mice in which P-388 tumor cells were intraperitoneally implanted, and the efficacy was expressed as ILS (%).
実施例１゜
５Ｆ２５８２Ｃモノメタンスルホン酸エステル（化合Ｉ
Ｊ ２ ）及び５Ｆ２５８２Ｃジメタンスルホン酸エス
テル（化合物１）の製造
５Ｆ２５８２Ｃ物質４０ｍｇを無水Ｎ、Ｎ−ジメチルメ
チム７ミド５ｍ／に溶解し、トリエチルアミン０．１１
１１及びメタンスルホン酸無水物５０ｍｇを加え。Example 1゜5F2582C monomethanesulfonic acid ester (compound I
J2) and Preparation of 5F2582C dimethane sulfonic acid ester (compound 1) 40 mg of 5F2582C substance was dissolved in 5 m/m of anhydrous N,N-dimethylmethim, and 0.11 g of triethylamine was added.
11 and 50 mg of methanesulfonic anhydride were added.
２５℃で１０分間反応させた０反応液にベンゼン２０ｍ
１及び水２０ｍ１’を加え抽出し、ベンゼン層を分離後
水洗し、無水硫酸ナトリウムを加えて乾燥した。硫酸ナ
トリウムをろ過して得たベンゼン溶液を減圧下に濃縮す
ると黄色固体が残留した０本物質をさらにシリカゾルク
ロマトグラフィー（溶媒系；ベンゼン／酢酸エチル＝
１７１ ）で精製し９次の三分画を得た。20 m of benzene was added to the 0 reaction solution that was reacted for 10 minutes at 25°C.
1 and 20 ml of water were added for extraction, and the benzene layer was separated, washed with water, and dried by adding anhydrous sodium sulfate. When the benzene solution obtained by filtering sodium sulfate was concentrated under reduced pressure, a yellow solid remained.This substance was further purified by silica sol chromatography (solvent system: benzene/ethyl acetate =
171) to obtain the 9th three fractions.
分１ｆｌ；５Ｆ２５８２Ｃジメタンスルホン酸エステル
（化合物１）Ｓｆｆ量４１ｍｇ
’ＨＮＨＲ（ＣＤＣムｔ ｐｐｍＧ９．３６（ｓ）、
８．６０（ｓ）＋ ６．９５（ｄ）６．８６（ｓ）、
５．７６（ｓ）、 ４．７７（ｄｄ）、 ４．６５（ｄ
）、 ４．４８（ｄｄ）４．２１（ａ＋）、 ４．０７
（ｓ）、 ３．９４（ｓ）、 ３．９１（ｓ）、 ３．
７８（ｓ）。min 1 fl; 5F2582C dimethane sulfonic acid ester (compound 1) Sff amount 41 mg 'HNHR (CDC mut ppm G9.36 (s),
8.60 (s) + 6.95 (d) 6.86 (s),
5.76(s), 4.77(dd), 4.65(d
), 4.48 (dd) 4.21 (a+), 4.07
(s), 3.94(s), 3.91(s), 3.
78(s).
３．３２（ｓ）、 ３．０３（ｓ）、 １．７０（ｓ）
ＦＤ ｍａｓｓ ； ６８２（Ｍ＋１）＋分画２．化合
物１及Ｖ２の混合物；収量６．３Ｂ分！３．５Ｆ２５８
２Ｃモノメタンスルホン酸エステル（化合物２）；収量
３．７ｍｇ’ＨＮＭＲ（ＣＤＣｊ！ｚｅ ｐＩＩＴｌｌ
）；９，７３（ｓ）＋ ８．６０（ｓ）＋ ６．９５（
ｄ）６．８３（ｓ）、 ５．７３（ｓ）、 ４．５９（
ｄ）、 ４．０７（Ｓ）＋ ４．０１（ｍ）＋３．９３
（ｓ）＋ ３．９１（ｍ）、 ３．９０（ｓ）、
３．８７（ｍ）＋ ３．７７（ｓ）＋３．３１（ｓ
）、 １．６９（ｓ）
ＦＤ ｍａｓｓ ： ６０３（Ｍ）＋
実施例２゜
３Ｆ２５８２Ｃモ／トルエンスルホン酸エステル（化合
物３）の製造
５Ｆ２５８２Ｃ物質１０Ｂを無水Ｎ、Ｎ−シメナルホル
ムアミド１．５社に溶解し、トリエチルアミン０．２ｍ
ｆ及びＰ−）ルエンスルホニルクロリｔ’ １０ｍｇを
加え、２５℃で３０分間反応させた。反応液にベンゼン
２０−及び水２０社を加え抽出し、ベンゼン層を分離後
、水洗、乾燥した。ベンゼン溶液を減圧下に濃縮して得
た残留物（黄色固体）をシリカゲルクロマトグラフィー
（溶媒系；ベンゼン／酢酸エチル＝ １／１ ）で精製
し、５Ｆ２５８２Ｃモ／−ｐ−）ルエンスルホン酸エス
テルヲｉｌｌり、 収量１２．６Ｈ’ＨＮＭＲ（ＣＤＣ
Ｉ、 ｐｐＬｌ）：９．３Ｈｓ）、 ８．２３（ｓ）、
７．８７（ｄ）。3.32(s), 3.03(s), 1.70(s)
FD mass; 682 (M+1) + fraction 2. Mixture of compounds 1 and V2; yield 6.3B! 3.5F258
2C monomethanesulfonic acid ester (compound 2); yield 3.7 mg'HNMR (CDCj!ze pIITll
);9,73(s)+8.60(s)+6.95(
d) 6.83(s), 5.73(s), 4.59(
d), 4.07 (S) + 4.01 (m) + 3.93
(s) + 3.91 (m), 3.90 (s),
3.87 (m) + 3.77 (s) + 3.31 (s
), 1.69(s) FD mass: 603(M)+ Example 2゜Production of 3F2582C mo/toluene sulfonic acid ester (compound 3) 5F2582C substance 10B was added to anhydrous N,N-cymenalformamide 1.5 Dissolve triethylamine 0.2m
f and P-) 10 mg of luenesulfonyl chloride t' was added and reacted at 25°C for 30 minutes. 20 parts of benzene and 20 parts of water were added to the reaction solution for extraction, and the benzene layer was separated, washed with water, and dried. The residue (yellow solid) obtained by concentrating the benzene solution under reduced pressure was purified by silica gel chromatography (solvent system: benzene/ethyl acetate = 1/1) to obtain 5F2582C mo/-p-) luenesulfonic acid ester. Yield 12.6H'HNMR (CDC
I, ppLl): 9.3Hs), 8.23(s),
7.87(d).
７．３８（ｃｌ）−６，９１（ｄ）、 ６．８２（ｓ）
、 ５．６５（ｓ）、 ４．５３（ｍ）。7.38 (cl) - 6,91 (d), 6.82 (s)
, 5.65 (s), 4.53 (m).
４．０７（ｓ）、３．９８（ｍ）、 ３．９３（ｓ）、
３．９０（ｓ）、 ３．７７（ｓ）。4.07 (s), 3.98 (m), 3.93 (s),
3.90 (s), 3.77 (s).
２．４７（ｓ）、 １．６４（ｓ）
ＦＤ ｍａｓｓ：６７９（ＨＪ’
実施例３゜
５Ｆ２５８２Ｃ硫酸エステル（化合物４）の製造５Ｆ２
５８２Ｃ物質５ＩＩ１ｇを無水ヒ’Ｊ ’） ンＩ Ｊ
に溶解し、無水硫酸−ピリジンコンプレックス１５ｍｇ
を加えて２５℃で１８時間反応させた０反応液を減圧下
に濃縮して得た残留物をセファデックスＬＨ−２０を用
いたカラムクロマトグラフィー（溶媒系；メタ／−ル／
水＝１／１）ｔ’Ｍ製Ｌ ＋ シリア＞ Ｙ ）ｋＴＬ
Ｃ（／ルク社、展開溶媒； クロロホルム／メタ７−ル
＝９７１）でＲＩ＆０．０３を示す分画を集め、メタノ
ールをｊ威圧下に除去後凍結乾燥して、５Ｆ２５８２Ｃ
硫酸エステノ喧ピリジン塩）を得た。収量６ｍｇ５ｌ
ｍａｓｓ； ６０６（Ｈ＋１７
実施例４゜
５Ｆ２５８２Ｃシクロプロパン誘導体（化合物５）の製
造
５Ｆ２５８２Ｃ物質５２ＩＩ１ｇを無水テトラヒドロ７
ラン１０ＩＩＩＩに溶解し、トリフェニルホスフィン３
９ｍｇ及びアゾジカルボン酸ジエチル３５ＩＩＩｇを加
えて２５℃で３時間反応させた０反応液を減圧下に濃縮
し。2.47 (s), 1.64 (s) FD mass: 679 (HJ' Example 3゜Production of 5F2582C sulfate ester (compound 4) 5F2
582C Substance 5II 1g is anhydrous
15 mg of anhydrous sulfuric acid-pyridine complex dissolved in
was added and reacted at 25°C for 18 hours. The residue obtained by concentrating the 0 reaction solution under reduced pressure was subjected to column chromatography using Sephadex LH-20 (solvent system: methanol/ol/
Water = 1/1) L + Syria made by t'M > Y) kTL
Fractions showing RI & 0.03 were collected using C (/LUKU Co., Ltd., developing solvent; chloroform/metha = 971), methanol was removed under pressure, and lyophilized to 5F2582C.
Sulfuric acid ester pyridine salt) was obtained. Yield 6mg5l
mass; 606 (H+17 Example 4゜Production of 5F2582C cyclopropane derivative (compound 5)
Triphenylphosphine 3 dissolved in Ran 10III
9 mg and 35III g of diethyl azodicarboxylate were added and reacted at 25° C. for 3 hours, and the reaction solution was concentrated under reduced pressure.
残留物をシリカゲルクロマトグラフィー（溶媒系；ベン
ゼン／酢酸エチル＝１／１）で精製し、粗粉末２４．２
Ｂを得た。この粉末をさらにセファデックスＬＨ−２０
を用いたカラムクロマトグラフィー（溶媒系；メタノー
ル）で精製し、シクロプロパン誘導体（化合物５）を得
た。ａ量１６． ＩＢ
ＩＨＩＩＨＲ（ＣＤＣム＊ ｐｐａ＋）：９．２５（ｄ
）、７．１８（ｓ）、８．９５（ｄ）。The residue was purified by silica gel chromatography (solvent system: benzene/ethyl acetate = 1/1) to give a crude powder of 24.2
I got a B. Add this powder to Sephadex LH-20
The product was purified by column chromatography (solvent system: methanol) to obtain a cyclopropane derivative (compound 5). A amount 16. IB IHIIHR (CDC* ppa+): 9.25 (d
), 7.18(s), 8.95(d).
６．７８（ｓ）、 ６．０５（ｓ）、 ４．４４（ｍ）
、 ４．０７（ｓ）、 ３．９４（ｓ）。6.78 (s), 6.05 (s), 4.44 (m)
, 4.07(s), 3.94(s).
３．８９（ｓ）＋ ３．７５（ｓ）＊ ２，２５（ｍ）
＋ １．６７（ｓ）、 １．５７（ｓ）Ｉ３ＣＮＨＲ（
ＣＤＣＮｓｗ Ｉｌｌ）ｍ）： １９４．７，１７９
，７，１６７．９゜１６５．０．１６４．３．１６１．
１．１５０，６．１４１．２．１３８．８゜１２８．０
．１２６．５．１２３．２．１１３．２．１１２．１．
ＩＯ２，１゜９フ、５． ７１．３． ６１．５
． ６１．２． ５６．２． ５５．３゜５３．
４． ３０．６． ２２，２． ２１．２ＦＤ ｍａｓ
ｓ： ５０７（岐
第１表 Ｐ−３８８細胞障害活性
５０．２
ＩＣ，。； Ｐ−３８８腫瘍細胞に対する５０％生育阻
害濃度（３７℃、５％Ｃ○２下で７２時間培１り第２表
Ｐ−３８８マウス白血病治療効果（−群５匹）化合物
投与量ｍｇ／ｋｔｔ ＩＬＳ（％）１
２、４ ４０
２ ０．５ ４０
２ ０．２５ １５
ＩＬＳ； （薬物投与群での平均延命日数／無投与群で
の平均生存日数）ｘｌｏｏ（％）
発明の効果
第１表および第２表より明らかなごとく１本発明で提供
される化合物は強い抗腫瘍活性を有し、抗腫瘍剤として
の用途が期待される。3.89 (s) + 3.75 (s) * 2,25 (m)
+ 1.67 (s), 1.57 (s) I3CNHR (
CDCNswIll)m): 194.7,179
,7,167.9°165.0.164.3.161.
1.150, 6.141.2.138.8°128.0
．． 126.5.123.2.113.2.112.1.
IO2, 1°9f, 5. 71.3. 61.5
．． 61.2. 56.2. 55.3°53.
4. 30.6. 22,2. 21.2FD mas
s: 507 (Table 1 P-388 cytotoxic activity 50.2 IC,.; Table P-388 mouse leukemia therapeutic effect (- group 5 mice) Compound Dose mg/ktt ILS (%) 1
2, 4 40 2 0.5 40 2 0.25 15 ILS; (Average survival days in the drug administration group/Average survival days in the non-administration group) xloo (%) Effect of the invention From Tables 1 and 2 As is clear, the compound provided by the present invention has strong antitumor activity and is expected to be used as an antitumor agent.
Claims (2)
−トリル基、メチル基もしくは水酸基を表す）もしくは
水素原子を表す、但しＸ及びＹが同時に水素原子である
場合を除く。〕で示されるＳＦ２５８２物質誘導体。(1) Formula [I] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [I] [Formula [I], X and Y are RSO_2- group (R is p
-represents a tolyl group, methyl group or hydroxyl group) or a hydrogen atom, except when X and Y are both hydrogen atoms. ] An SF2582 substance derivative represented by:
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63103782A JP2562935B2 (en) | 1988-04-28 | 1988-04-28 | Antitumor substance SF2582 derivative |
| US07/344,738 US4994578A (en) | 1987-11-27 | 1989-04-28 | Certain anti-tumor duocarmycin antibiotics from streptomyces |
| DE89107799T DE68905644T2 (en) | 1988-04-28 | 1989-04-28 | Antibiotic substance with anti-tumor effects. |
| EP89107799A EP0339681B1 (en) | 1988-04-28 | 1989-04-28 | Antitumor antibiotic substance |
| US07/520,424 US5037993A (en) | 1987-11-27 | 1990-05-08 | Sulfonyl derivatives of an antibiotic substance isolated from streptomyces |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63103782A JP2562935B2 (en) | 1988-04-28 | 1988-04-28 | Antitumor substance SF2582 derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01275581A true JPH01275581A (en) | 1989-11-06 |
| JP2562935B2 JP2562935B2 (en) | 1996-12-11 |
Family
ID=14362984
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63103782A Expired - Lifetime JP2562935B2 (en) | 1987-11-27 | 1988-04-28 | Antitumor substance SF2582 derivative |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0339681B1 (en) |
| JP (1) | JP2562935B2 (en) |
| DE (1) | DE68905644T2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02119787A (en) * | 1988-07-22 | 1990-05-07 | Kyowa Hakko Kogyo Co Ltd | Novel compound dc-89 and production thereof |
| US6651082B1 (en) | 1998-08-03 | 2003-11-18 | International Business Machines Corporation | Method for dynamically changing load balance and computer |
| JP2009525322A (en) * | 2006-02-02 | 2009-07-09 | シンタルガ・ビーブイ | Water-soluble CC-1065 analog and its conjugate |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5084468A (en) * | 1988-08-11 | 1992-01-28 | Kyowa Hakko Kogyo Co., Ltd. | Dc-88a derivatives |
| US5008271A (en) * | 1988-10-21 | 1991-04-16 | Kyowa Hakko Kogyo Co., Ltd. | DC-88A derivatives |
| JP2510335B2 (en) * | 1989-07-03 | 1996-06-26 | 協和醗酵工業株式会社 | DC-88A derivative |
| US5214065A (en) * | 1990-06-11 | 1993-05-25 | Kyowa Hakko Kogyo Co., Ltd. | Dc-89 derivatives |
| US5248692A (en) * | 1990-06-11 | 1993-09-28 | Kyowa Hakko Kogyo Co., Ltd. | DC-89 derivatives as anti-tumor agents |
| EP0499130A1 (en) * | 1991-02-15 | 1992-08-19 | Kyowa Hakko Kogyo Co., Ltd. | DC-89 derivatives |
| EP0520435A3 (en) * | 1991-06-28 | 1993-05-05 | Kyowa Hakko Kogyo Co., Ltd. | Dc-89 derivatives |
| CA2589346A1 (en) | 2004-12-09 | 2006-06-15 | Dow Global Technologies Inc. | Enzyme stabilization |
| EP3075832B1 (en) | 2015-03-30 | 2021-04-14 | Dalli-Werke GmbH & Co. KG | Manganese-amino acid compounds in cleaning compositions |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1238907A (en) * | 1984-02-21 | 1988-07-05 | Robert C. Kelly | 1,2,8,8a-tetrahydrocyclopropa¬c|pyrrolo(3,2-e)- indol-4(5h)-ones and related compounds |
| EP0340243B1 (en) * | 1986-12-19 | 1994-09-28 | The Upjohn Company | Cc-1065 analogs |
-
1988
- 1988-04-28 JP JP63103782A patent/JP2562935B2/en not_active Expired - Lifetime
-
1989
- 1989-04-28 DE DE89107799T patent/DE68905644T2/en not_active Expired - Fee Related
- 1989-04-28 EP EP89107799A patent/EP0339681B1/en not_active Expired - Lifetime
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02119787A (en) * | 1988-07-22 | 1990-05-07 | Kyowa Hakko Kogyo Co Ltd | Novel compound dc-89 and production thereof |
| US6651082B1 (en) | 1998-08-03 | 2003-11-18 | International Business Machines Corporation | Method for dynamically changing load balance and computer |
| JP2009525322A (en) * | 2006-02-02 | 2009-07-09 | シンタルガ・ビーブイ | Water-soluble CC-1065 analog and its conjugate |
| JP2013227326A (en) * | 2006-02-02 | 2013-11-07 | Syntarga Bv | Water-soluble cc-1065 analog and conjugate thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| DE68905644T2 (en) | 1993-10-28 |
| JP2562935B2 (en) | 1996-12-11 |
| EP0339681A3 (en) | 1990-01-31 |
| DE68905644D1 (en) | 1993-05-06 |
| EP0339681B1 (en) | 1993-03-31 |
| EP0339681A2 (en) | 1989-11-02 |
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